Abstract
Glutamate/N-methyl-d-aspartate (NMDA) receptor-mediated neurotoxicity involves cyclooxygenase (COX)-2. We demonstrate that this neurotoxicity reflects activation of COX-2 by S-nitrosylation after selective binding of neuronal nitric oxide synthase (nNOS) to COX-2. nNOS, via its PDZ domain, binds COX-2 with the generated NO S-nitrosylating and activating the enzyme. Selective disruption of nNOS-COX-2 binding prevents NMDA neurotoxicity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Biotin / chemistry
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Brain / metabolism
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Cell Death
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Cerebellum / metabolism
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Cyclooxygenase 2 / metabolism*
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Enzyme Activation
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Humans
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Membrane Proteins / chemistry
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Mice
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N-Methylaspartate / toxicity*
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Neurons / metabolism
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Nitric Oxide Synthase Type II / metabolism
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Protein Binding
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Receptors, N-Methyl-D-Aspartate / chemistry*
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Receptors, N-Methyl-D-Aspartate / metabolism
Substances
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Membrane Proteins
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Receptors, N-Methyl-D-Aspartate
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N-Methylaspartate
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Biotin
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2